1. Field of Invention
This invention relates to a method of improving the memory of living animals with certain arylamidoazabicycloalkanes. The invention contemplates the treatment of memory deficiencies and disorders associated with Alzheimers disease and other forms of sinility.
2. Information Disclosure Statement
Various chemicals such as physostigmine, arecholine, choline or piracetam have been reported to facilitate memory in animals, KIRK OTHMER, ENCYCL. CHEM. TECHNOL., 3rd Ed. (1981) Vol. 15, pp 132-142 and ANNUAL REPORTS IN MEDICINAL CHEMISTRY (1984) Vol. 19, pp 31-43. The cardiovascular drug procainamide has been tested for learning enhancement activity in experimental animals of different ages and has been said to improve learning deficits in aging rats KIRK OTHMER ibid p. 139. Ergoloid Mesylates have been used in treatment of impaired mental function in the elderly. The ergoloid mesylates may in some cases give rise to nausea during treatment for mental impairment and may possess .alpha.-adrenergic blocking activity. THE MERCK INDEX 10th Ed. 3596 and PHYSICIANS DESK REF., 38th Ed. 1984, pp 911-912. In contrast, certain of the compounds of the formula used in the present invention have antinauseant properties and are not .alpha.-adrenergic blocking agents, cholinomimetics, cholinesterase inhibitors or stimulants.
2-Alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides and their use in a method for increasing gastric emptying and alleviating emesis, particularly emesis due to administration of platinum and anticancer drugs such as cisplatin are disclosed in copending U.S. application Ser. No. 597,275 filed Apr. 6, 1984. Certain of these 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides are also disclosed in Fr. Pat. No. 2.529.548 and European Patent application No. 099.789A and their use as gastrointestinal motility accelerators and as potentiators for medicaments, especially analgesics such as aspirin and paracetamol is also disclosed. Certain of the compounds are also disclosed as useful as analgesics-antipsychotics in Brit. Patent application No. 2,125,398A.
Syntheses of certain N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides have been reported by E. E. Mikhalina, et al., in KHIM-FARM. Zh. (1973) 7 (8) p. 20-24: C.A. 79 146358a. The compounds were reported to possess narcotic, nerve center blocking and hypotensive activity.
The compound 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-chloro-5-trifluoromethyl-benzami de has been reported in U.S. Pat. No. 4,093,734 in a class of compounds said to be anxiolytics, anticonvulsants, antiemetics and antiulcerogenics.
Certain of the compounds encompassed by Formula I and useful in the method of the present invention and exemplified by N-(7-octahydroindolizinyl)benzamides and N-(1 and 2-quinolizinyl)benzamides are disclosed by structure, method of synthesis and characterization in U.S. Pat. No. 4,213,983 as being useful in treating gastro-intestinal misfunctions. Still other compounds of Formula I useful in the present invention and exemplified by 4-amino-4-chloro-2-methoxy-N-[4'-.alpha.,.beta.-(1'-aza-2'-.alpha.-phenyl- 6'-.alpha.-N-bicyclo[4,3,0]decyl)]benzamide and 4-amino-5-chloro-2-methoxy-N-[7'.beta.-(9'.beta.-methyl-1'-aza-5'.alpha.-H -bicyclo[4,3,0]nonyl)]benzamide are disclosed by structure, method of synthesis and characterization in European patent application 0067565A1 as dopamine antagonists for treating impaired gastric motility.